A Self-Regulatory System of Interlinked Signaling Feedback Loops Controls Mouse Limb Patterning

Embryogenesis depends on self- regulatory interactions between spatially separated signaling centers, but few of these are well understood. Limb development is regulated by epithelial- mesenchymal (e-m) feedback loops between sonic hedgehog ( SHH) and fibroblast growth factor ( FGF) signaling involving the bone morphogenetic protein ( BMP) antagonist Gremlin1 ( GREM1). By combining mouse molecular genetics with mathematical modeling, we showed that BMP4 first initiates and SHH then propagates e- m feedback signaling through differential transcriptional regulation of Grem1 to control digit specification. This switch occurs by linking a fast BMP4/ GREM1 module to the slower SHH/ GREM1/ FGF e- m feedback loop. This self- regulatory signaling network results in robust regulation of distal limb development that is able to compensate for variations by interconnectivity among the three signaling pathways.